tbuckley/cabot-search huggingface dataset:
Pharmacogenomics Beyond Single Common Genetic Variants: The Way Forward
Authors: Volker M. Lauschke, Yitian Zhou, Magnus Ingelman-Sundberg
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics.
Clonally expanded CD38 <sup>hi</sup> cytotoxic CD8 T cells define the T cell infiltrate in checkpoint inhibitor–associated arthritis
Authors: Runci Wang, Anvita Singaraju, Kathryne E. Marks, Lorien Shakib, Garrett Dunlap, Ifeoluwakiisi Adejoorin, Stinne R. Greisen, Lin Chen, Aidan K. Tirpack, Carlos Aude, Miriam R. Fein, Derrick J. Todd, Lindsey MacFarlane, Susan M. Goodman, Edward F. DiCarlo, Elena M. Massarotti, Jeffrey A. Sparks, A. Helena Jonsson, Michael B. Brenner, Michael A. Postow, Karmela K. Chan, Anne R. Bass, Laura T. Donlin, Deepak A. Rao
Journal: Science Immunology (2023)

Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti–PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38 hi CD127 − CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38 hi phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38 hi CD127 − T cells, which were frequently bound by the therapeutic anti–PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
Targeting the Immunoglobulin IGSF9 Enhances Antitumor T-cell Activity and Sensitivity to Anti–PD-1 Immunotherapy
Authors: Yifan Liu, Hongying Wang, Xinyu Zhao, Jiashen Zhang, Zhiling Zhao, Xia Lian, Juan Zhang, Feng Kong, Tao Hu, Ting Wang, Xiaohua Li, Lei Wang, Dapeng Wang, Chunling Li, Huiwen Luan, Xiaoli Liu, Chunyan Wang, Yun Jiang, Xiaomin Li, Fangmin Li, Shuhao Ji, Yaopeng Wang, Zunling Li
Journal: Cancer Research (2023)

Abstract Immune checkpoints modulate the immune response and represent important immunotherapy targets for cancer treatment. However, as many tumors are resistant to current immune checkpoint inhibitors, the discovery of novel immune checkpoints could facilitate the development of additional immunotherapeutic strategies to improve patient responses. Here, we identified increased expression of the adhesion molecule immunoglobulin superfamily member 9 (IGSF9) in tumor cells and tumor-infiltrating immune cells across multiple cancer types. IGSF9 overexpression or knockout in tumor cells did not alter cell proliferation in vitro or tumor growth in immunocompromised mice. Alternatively, IGSF9 deficient tumor cells lost the ability to suppress T-cell proliferation and exhibited reduced growth in immunocompetent mice. Similarly, growth of tumor cells was reduced in IGSF9 knockout syngeneic and humanized mice, accompanied by increased tumor-infiltrating T cells. Mechanistically, the extracellular domain (ECD) of IGSF9 bound to T cells and inhibited their proliferation and activation, and the tumor-promoting effect of IGSF9 ECD was reversed by CD3+ T-cell depletion. Anti-IGSF9 antibody treatment inhibited tumor growth and enhanced the antitumor efficacy of anti-programmed cell death protein 1 immunotherapy. Single-cell RNA sequencing revealed tumor microenvironment remodeling from tumor promoting to tumor suppressive following anti-IGSF9 treatment. Together, these results indicate that IGSF9 promotes tumor immune evasion and is a candidate immune checkpoint target. Significance: IGSF9 is an immune checkpoint regulator that suppresses T-cell activation in cancer and can be targeted to stimulate antitumor immunity and inhibit tumor growth.
Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Authors: Elise G. Viox, Timothy N. Hoang, Amit A. Upadhyay, Rayhane Nchioua, Maximilian Hirschenberger, Zachary Strongin, Gregory K. Tharp, Maria Pino, Kevin Nguyen, Justin L. Harper, Matthew Gagne, Shir Marciano, Arun K. Boddapati, Kathryn L. Pellegrini, Arpan Pradhan, Jennifer Tisoncik-Go, Leanne S. Whitmore, Kirti A. Karunakaran, Melissa Roy, Shannon Kirejczyk, Elizabeth H. Curran, Chelsea Wallace, Jennifer S. Wood, Fawn Connor-Stroud, Emily A. Voigt, Christopher M. Monaco, David E. Gordon, Sudhir P. Kasturi, Rebecca D. Levit, Michael Gale, Thomas H. Vanderford, Guido Silvestri, Kathleen Busman-Sahay, Jacob D. Estes, Monica Vaccari, Daniel C. Douek, Konstantin M.J. Sparrer, R. Paul Johnson, Frank Kirchhoff, Gideon Schreiber, Steven E. Bosinger, Mirko Paiardini
Journal: Science Immunology (2023)

Type I interferons (IFN-I) are critical mediators of innate control of viral infections but also drive the recruitment of inflammatory cells to sites of infection, a key feature of severe coronavirus disease 2019. Here, IFN-I signaling was modulated in rhesus macaques (RMs) before and during acute SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection using a mutated IFN-α2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. IFNmod treatment in uninfected RMs was observed to induce a modest up-regulation of only antiviral IFN-stimulated genes (ISGs); however, in SARS-CoV-2–infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. IFNmod treatment resulted in a potent reduction in SARS-CoV-2 viral loads both in vitro in Calu-3 cells and in vivo in bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes of RMs. Furthermore, in SARS-CoV-2–infected RMs, IFNmod treatment potently reduced inflammatory cytokines, chemokines, and CD163 + MRC1 − inflammatory macrophages in BAL and expression of Siglec-1 on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. Using an intervention targeting both IFN-α and IFN-β pathways, this study shows that, whereas early IFN-I restrains SARS-CoV-2 replication, uncontrolled IFN-I signaling critically contributes to SARS-CoV-2 inflammation and pathogenesis in the moderate disease model of RMs.
Integrated Design Fabrication and Control of a Bioinspired Multimaterial Soft Robotic Hand
Authors: Samuel Alves, Mihail Babcinschi, Afonso Silva, Diogo Neto, Diogo Fonseca, Pedro Neto
Journal: Cyborg and Bionic Systems (2023)

Machines that mimic humans have inspired scientists for centuries. Bioinspired soft robotic hands are a good example of such an endeavor, featuring intrinsic material compliance and continuous motion to deal with uncertainty and adapt to unstructured environments. Recent research led to impactful achievements in functional designs, modeling, fabrication, and control of soft robots. Nevertheless, the full realization of life-like movements is still challenging to achieve, often based on trial-and-error considerations from design to fabrication, consuming time and resources. In this study, a soft robotic hand is proposed, composed of soft actuator cores and an exoskeleton, featuring a multimaterial design aided by finite element analysis (FEA) to define the hand geometry and promote finger's bendability. The actuators are fabricated using molding, and the exoskeleton is 3D-printed in a single step. An ON-OFF controller keeps the set fingers' inner pressures related to specific bending angles, even in the presence of leaks. The FEA numerical results were validated by experimental tests, as well as the ability of the hand to grasp objects with different shapes, weights, and sizes. This integrated solution will make soft robotic hands more available to people, at a reduced cost, avoiding the time-consuming design-fabrication trial-and-error processes.
Burden of non-communicable diseases among adolescents and young adults aged 10–24 years in the South-East Asia and Western Pacific regions, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019
Authors: Huan Wang, Yi Song, Jun Ma, Sheng Ma, Lijuan Shen, Yangmu Huang, Pugazhenthan Thangaraju, Zarrin Basharat, Yifei Hu, Yuan Lin, Amy E Peden, Susan M Sawyer, Hao Zhang, Zhiyong Zou
Journal: The Lancet Child & Adolescent Health (2023)
Polysaccharide hydrogel platforms as suitable carriers of liposomes and extracellular vesicles for dermal applications
Authors: Leila Pourtalebi Jahromi, Markus Rothammer, Gregor Fuhrmann
Journal: Advanced Drug Delivery Reviews (2023)

Lipid-based nanocarriers have been extensively investigated for their application in drug delivery. Particularly, liposomes are now clinically established for treating various diseases such as fungal infections. In contrast, extracellular vesicles (EVs) - small cell-derived nanoparticles involved in cellular communication - have just recently sparked interest as drug carriers but their development is still at the preclinical level. To drive this development further, the methods and technologies exploited in the context of liposome research should be applied in the domain of EVs to facilitate and accelerate their clinical translation. One of the crucial steps for EV-based therapeutics is designing them as proper dosage forms for specific applications. This review offers a comprehensive overview of state-of-the-art polysaccharide-based hydrogel platforms designed for artificial and natural vesicles with application in drug delivery to the skin. We discuss their various physicochemical and biological properties and try to create a sound basis for the optimization of EV-embedded hydrogels as versatile therapeutic avenues.
Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study
Authors: Ahmed Abdelhak, Franziska Petermeier, Pascal Benkert, Sabine Schädelin, Johanna Oechtering, Aleksandra Maleska Maceski, Michael Kabesch, Tobias Geis, Otto Laub, Georg Leipold, Claudio Gobbi, Chiara Zecca, Ari Green, Hayrettin Tumani, Eline Willemse, Heinz Wiendl, Cristina Granziera, Ludwig Kappos, David Leppert, Emmanuelle Waubant, Sven Wellmann, Jens Kuhle
Journal: The Lancet Neurology (2023)
Descemet Stripping Automated Endothelial Keratoplasty versus Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy
Authors: Andreas Viberg, Branka Samolov, Berit Byström
Journal: Ophthalmology (2023)

To compare the outcome between posterior lamellar corneal transplant procedures for Fuchs endothelial corneal dystrophy, taking preoperative patient characteristics in consideration. Surgical methods compared were Descemet membrane endothelial keratoplasty (DMEK), Descemet stripping automated endothelial keratoplasty (DSAEK), and DSAEK with concomitant cataract surgery (phacoemulsification plus DSAEK).Registry-based study with propensity score matching.One thousand six hundred seventy-seven patients from all Swedish corneal transplantation units treated from 2012 through 2019.All patients undergoing endothelial keratoplasty performed from 2012 through 2019 with completed 2-year follow-up data reported to The Swedish Corneal Transplant Register were included, totaling 1677 patients. Three comparable groups (DMEK, DSAEK, and phacoemulsification plus DSAEK) with 216 patients in each group were generated with propensity score matching based on preoperative visual acuity, age, sex, year of surgery, and preoperative risk factors such as inflammation, vascularization, and glaucoma.Best-corrected visual acuity (BCVA) at the 2-year follow-up, frequency of graft dislocation, graft rejection episodes, and graft failure within 2 years including primary graft failure.The preoperative corneal status was affected more severely in the DSAEK group before matching. In the matched groups, the median BCVA 2 years after surgery was 0.1 logarithm of the minimum angle of resolution (logMAR) in both the DMEK and the phacoemulsification plus DSAEK groups and 0.15 logMAR in the DSAEK group (P = 0.001). The frequency of graft dislocation was higher among the patients undergoing phacoemulsification plus DSAEK, but the frequency of graft failure and primary graft failure was higher in the DMEK group.Visual acuity improved in most patients (90%) with all 3 surgical methods. However, DMEK and phacoemulsification plus DSAEK reached higher levels of visual acuity 2 years after surgery, and phacoemulsification plus DSAEK was superior considering graft survival rate. All 3 surgical procedures showed both strengths and weaknesses, suggesting that the choice of surgical method should be individualized, taking into consideration not only the cornea, but each patient's complete medical status as well as the entire course of postoperative medical care.The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial
Authors: Christopher W Ryan, Catherine M Tangen, Elisabeth I Heath, Mark N Stein, Maxwell V Meng, Ajjai S Alva, Sumanta K Pal, Igor Puzanov, Joseph I Clark, Toni K Choueiri, Neeraj Agarwal, Robert G Uzzo, Naomi B Haas, Timothy W Synold, Melissa Plets, Ulka N Vaishampayan, Brian M Shuch, Ian M Thompson, Primo N Lara
Journal: The Lancet (2023)
Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD
Authors: Eva M. Fernández-Sáez, Maite Losarcos, Sara Becerril, Víctor Valentí, Rafael Moncada, Marina Martín, María A. Burrell, Victoria Catalán, Javier Gómez-Ambrosi, Carmen Mugueta, Inmaculada Colina, Camilo Silva, Javier Escalada, Gema Frühbeck, Amaia Rodríguez
Journal: Metabolism (2023)

The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery.Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions.Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation.Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
Ferric derisomaltose and tranexamic acid, combined or alone, for reducing blood transfusion in patients with hip fracture (the HiFIT trial): a multicentre, 2 × 2 factorial, randomised, double-blind, controlled trial
Authors: Sigismond Lasocki, Xavier Capdevila, Bruno Vielle, Benjamin Bijok, Maria Lahlou-Casulli, Vincent Collange, Nicolas Grillot, Marc Danguy des Deserts, Alexis Duchalais, Bertrand Delannoy, Bertrand Drugeon, Pierre Bouzat, Jean-Stéphane David, Louis Rony, Thibault Loupec, Maxime Léger, Emmanuel Rineau, Guillaume Bouhours, Sigismond Lasocki, Adeline Lebail, Maxime Léger, Elsa Parot-Schinkel, Emmanuel Rineau, Louis Rony, Bruno Vielle, Xavier Capdevilla, Thibault Loupec, Benjamin Mounet, Fabien Swisser, Marc Danguy des Deserts, Raphael Cinotti, Nicolas Grillot, Karim Asehnoune, Antoine Roquilly, Hélène Beloeil, Maria Lahlou-Casulli, Vincent Collange, Sébastien Parent, Bertrand Delannoy, Olivier Desebbe, Alexis Duchalais, Bertrand Drugeon, Jeremy Guenezan, Pierre Bouzat, Sabine Drevet, Gaetan Gavazzi, Jules Greze, Benjamin Bijok, Delphine Garrigue, Jean-Stéphane David
Journal: The Lancet Haematology (2023)
Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases
Authors: Nikolaos Perakakis, Hani Harb, Benjamin G Hale, Zsuzsanna Varga, Charlotte Steenblock, Waldemar Kanczkowski, Vasileia Ismini Alexaki, Barbara Ludwig, Peter Mirtschink, Michele Solimena, Nicole Toepfner, Sebastian Zeissig, Manuel Gado, Irene Alma Abela, Felix Beuschlein, Giatgen A Spinas, Claudia Cavelti-Weder, Philipp A Gerber, Michael Huber, Alexandra Trkola, Milo A Puhan, Wendy Wei-Lynn Wong, Andreas Linkermann, Viswanathan Mohan, Hendrik Lehnert, Peter Nawroth, Triantafyllos Chavakis, Geltrude Mingrone, Christian Wolfrum, Annelies S Zinkernagel, Stefan R Bornstein
Journal: The Lancet Diabetes & Endocrinology (2023)
Utility of nailfold capillary assessment for predicting pustulotic arthro-osteitis in palmoplantar pustulosis based on a prospective cohort study
Authors: Takemichi Fukasawa, Takashi Yamashita, Atsushi Enomoto, Satoshi Toyama, Asako Yoshizaki-Ogawa, Shoko Tateishi, Hiroko Kanda, Kiyoshi Miyagawa, Shinichi Sato, Ayumi Yoshizaki
Journal: Journal of the American Academy of Dermatology (2023)
Frequency of HLA-DR+CD38hi T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders
Authors: Thinh H. Nguyen, Deepak Kumar, Chengyu Prince, Dylan Martini, Jocelyn R. Grunwell, Taylor Lawrence, Trenton Whitely, Karin Chappelle, Satheesh Chonat, Sampath Prahalad, Michael Briones, Shanmuganathan Chandrakasan
Journal: Journal of Allergy and Clinical Immunology (2023)
The Association Between a Mediterranean Diet and Symptoms of Irritable Bowel Syndrome
Authors: Ellie Y. Chen, Swapna Mahurkar-Joshi, Cathy Liu, Nancee Jaffe, Jennifer S. Labus, Tien S. Dong, Arpana Gupta, Shravya Patel, Emeran A. Mayer, Lin Chang
Journal: Clinical Gastroenterology and Hepatology (2023)

Low adherence to Mediterranean diet (MD) has been shown to be associated with a higher prevalence of irritable bowel syndrome (IBS), but its association with IBS symptoms is not established. We aim to assess the association between MD and IBS symptoms, identify components of MD associated with IBS symptoms, and determine if a symptom-modified MD is associated with changes in the gut microbiome.
Benchmarking common uncertainty estimation methods with histopathological images under domain shift and label noise
Authors: Hendrik A. Mehrtens, Alexander Kurz, Tabea-Clara Bucher, Titus J. Brinker
Journal: Medical Image Analysis (2023)

In the past years, deep learning has seen an increase in usage in the domain of histopathological applications. However, while these approaches have shown great potential, in high-risk environments deep learning models need to be able to judge their uncertainty and be able to reject inputs when there is a significant chance of misclassification. In this work, we conduct a rigorous evaluation of the most commonly used uncertainty and robustness methods for the classification of Whole Slide Images, with a focus on the task of selective classification, where the model should reject the classification in situations in which it is uncertain. We conduct our experiments on tile-level under the aspects of domain shift and label noise, as well as on slide-level. In our experiments, we compare Deep Ensembles, Monte-Carlo Dropout, Stochastic Variational Inference, Test-Time Data Augmentation as well as ensembles of the latter approaches. We observe that ensembles of methods generally lead to better uncertainty estimates as well as an increased robustness towards domain shifts and label noise, while contrary to results from classical computer vision benchmarks no systematic gain of the other methods can be shown. Across methods, a rejection of the most uncertain samples reliably leads to a significant increase in classification accuracy on both in-distribution as well as out-of-distribution data. Furthermore, we conduct experiments comparing these methods under varying conditions of label noise. Lastly, we publish our code framework to facilitate further research on uncertainty estimation on histopathological data.
A novel antibody-KSP inhibitor conjugate improves KSP inhibitor efficacy in vitro and in vivo
Authors: Yiquan Li, Zihao Wang, Yuchao Dong, Xiaoyang Yu, Jing Lu, Ningyi Jin, Chao Shang, Xiao Li, Shiyong Fan
Journal: Biomaterials (2023)

Many clinical trials of kinesin spindle protein (KSP) inhibitors have failed due to issues such as high toxicity and a short circulation half-life in vivo. To address the limitations of current KSP inhibitors and thus broad its use in antitumor therapy, this study applied antibody-drug conjugate (ADC) technology to the KSP inhibitor SB-743921, which was coupled with the HER2-specific antibody trastuzumab using a cathepsin B-dependent valine-alanine (Val-Ala, VA) dipeptide-type linker to generate H2-921. Ex vivo and in vivo analyses of H2-921 showed an increased half-life of SB-743921 and prolonged contact time with tumor cells. Furthermore, H2-921 induced apoptosis and incomplete autophagy in HER2-positive cells. In the in vivo analyses, H2-921 had significant tumor-targeting properties, and tumor inhibition by H2-921 was greater than that by traditional KSP inhibitors but similar to that by the positive control drug T-DM1. In conclusion, this study describes a novel application of ADC technology that enhances the antitumor effects of a KSP inhibitor and thus may effectively address the poor clinical efficacy of KSP inhibitors.